Heterocyclic spiro compounds

ABSTRACT

Compounds of the class of spiro(norbornane-2,3&#39;&#39;-piperidines), spiro(bicyclo(2.2.2)octane-2,3&#39;&#39;-piperidines), and corresponding spiro-pyrrolidine derivatives which are unsubstituted at the ring nitrogen atom or substituted by neutral or basic radicals, and the pharmaceutically acceptable acid addition salts of these new compounds possess valuable pharmacological properties and are active ingredients for pharmaceutical compositions. In particular, these new compounds have an antiviral activity. Specific embodiments are (1RS,2RS,4SR)-spiro(norbornane-2,3&#39;&#39;piperidine)-hydrochloride and 1&#39;&#39;-(2-(2-azaspiro(5.5)undec-2-yl)ethyl)-spiro(bicyclo(2.2.2)octane-2,3&#39;&#39; -piperidine)dihydrochloride.

United States Patent [191 Schaffner et al.

[451 Oct. 21, 1975 HETEROCYCLIC SPIRO COMPOUNDS Switzerland [73] Assignee: CIBA-GEIGY Corporation, Ardsley,

[22] Filed: May 2,1973

21 Appl. No.: 356,545

[30] Foreign Application Priority Data May 4, 1972 Switzerland 6613/72 [52] US. CL... 260/247.2 A; 260/2475 R; 260/281; 260/293.56; 260/326.38; 260/3265 E;

[51] Int. Cl. C07D 221/20 [58] Field of Search... 260/247.5 R, 293.56, 326.38, 260/3265 E, 326.5 FM, 326.62, 247.2 A, 281

[56] References Cited UNITED STATES PATENTS 2,931,805 4/1960 Weinstock 260/2393 Primary Examiner-G. Thomas Todd Attorney, Agent, or FirmJoseph G. Kolodny; John J. Maitner; Theodore O. Groeger [57] ABSTRACT Compounds of the class of spiro[norbornane-2,3- piperidines], spiro[bicyclo[2.2.2]octane-2,3- piperidines], and corresponding spiro-pyrrolidine derivatives which are unsubstituted at the ring nitrogen atom or substituted by neutral or basic radicals, and the pharmaceutically acceptable acid addition salts of these new compounds possess valuable pharmacolog ical properties and are active ingredients for pharmaceutical compositions. In particular, these new compounds have an antiviral activity. Specific embodi' ments are (1RS,2RS,4SR)-spiro[norbornane-2,3'- piperidinel-hydrochloride and 1 2-( 2- azaspiro[5 .5 ]'undec-2-yl )-ethyl spiro[bicyclo[2.2.2]octane-2,3'-piperidine]- dihydrochloricle.

8 Claims, No Drawings HETEROCYCLIC SPIRO COMPOUNDS The present invention relates to processes for the production of new heterocyclic spiro compounds and their acid addition salts, to these new substances themselves, as well as to pharmaceuticalpreparations containing them and to the use thereof.

The compounds accordingto the invention correspond to the general formula I v H C c\ NR, (1)

(CH c v CH2 wherein alk-N (la) wherein j r 'alk stands for a nongemi'nal, bivalent, saturated aliphatic hydrocarbon radical'having 2 to carbon atoms,.

or for the 2-hydroxy-trimethylene radical,

R and R have the meanings given for R,, with exception of the radical of the partial formula la. and can together also represent a tetramethylene to hexamethylene radical optionally substituted by lower alkyl groups, the ethyleneoxyethylene radicaL or a tetraor pentamethylene radical substituted, for its part, in the 2-position by the tetramethylene, pentamethylene, 1,4- methanopentamethylene or l,4-ethanopentamethylene radical,

m represents 0 or I, and

n represents or 2.

In the compounds of the general formula 1, R as the alkyl group or alkenyl group is, for example, the methyl, propyl, isopropyl, butyl, isobutylppent yl. isopentyl, neopentyl or hexyl group, but'preferably the ethyl group; as the alkenyl group it is, forexample, the allyl, l-methylallyl. 2-methylallyl, Z-butenyl, 1,2- dimethylallyl, 3-methyl-2-butenyl Z-pentenyl, 2,3-dimethyl-2-butenyl or Z-hexenyl group, and as 'an optionally chlorine-substituted hydroxyalkylgroup, R1 is, for example, the 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-, ll-hydi'bxyor 4- hydroxybutyl, 2-methyl-3-hydroxypropyl, Z-hydroxyor S-hydroxypentyl, 2,2-dimethyl-3-hydroxypropyl, 2- hydroxyhexyl. 6-hydroxyhexyl, l-methyl-4- h'ydroxypentyl. 3-chloro-2-hydroxybutyl, 4-chloro-2- hydroxybutyl, 3-chloro-2-hydroxy-2-methylpropyl or 5-chloro-2-hydroxy-pentyl group. and preferably the 3-chloro-2-hydroxypropyl group. Optionally substituted phenyl-(lower alkyl) groups contain in their lower alkyl group preferably 1 to 4 carbon atoms and are, for example, the phenethyl, a-methylbenzyl, 2- phenylpropyl. a-methylphenethyl, Z-phenylbutyl or 4- phenylbutyl group, and preferably the benzyl or 3- phenylpropyl group, as well as corresponding groups substituted as defined in the phenyl radical, such as, eg the o-, mor p-fluorobenzyl group. the 0-; mor pchlorobenzyl group. the 2,4-, 2.5-, 2.6- or 3.4- dichlorobenzyl group, the 0-, mor p-bromobenzyl group. the 0-, mor p-methylbenzyl group. the pethylbenzyl or p-isopropylbenzyl group. the o-. mor p-methoxybenzyl group. the p-ethoxybenzyl. ppropoxybenzyl, p-isopropoxybenzyl. p-butoxybenzyl. 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl or 3,4,5- trimethoxybenzyl group, whereby the 3.4- dichlorobenzyl group is of particular importance.

As a nongeminal, bivalent, saturated aliphatic hydrocarbon radical, alk in the partial formula la is, for example, the propylene, tetramethylene. 2- methyltrimethylene, lor 3-methyltrimethylene, pentamethylene or 2,2-dimethyltrimethylene group, and preferably the trimethylene and particularly the ethylene group. The symbols R and R can represent, for example, the groups mentioned above as examples for R and are, in particular, hydrogen atoms, methyl or benzyl groups. NRgRg; can be. for example. the

pyrrolidinyl, piperidino, Z-methylpiperidino, 2,6- dimethylpiperidino, hexahydro-lH-azepin-l-yl, 2- azaspiro[4.4]non-2-yl. 2-azaspiro[4.5]dec-2-yl, 7-

azaspiro[4.5 ]dec-7-yl. 2-azaspiro[5.5]undec-Z-yl. spiro[nor bornane-2,3 -pyrrolidin[-l '-yl, spirolnorbornane-2,3'-piperidin[-l -yl, spirolbicyclol 2.2.2loctane- 2,3'-pyrrolidin[-l'-yl or spiro[bicyclo[2.2.2]octane- 2,3,'-pyrrolidin[-l'-yl group, whereby the 2- azaspiro[5.5]undec-2-yl group is of special importance. I

- The compounds of the general formula l and their addition salts with inorganic and organic acids possess valuable pharmacological properties, particularly antiviral activity, and at the same time have relatively low toxicity. Compounds of particular importance are compounds of the general formula I wherein m is l and n 1 or 2. Preferred compounds within this group are those in which R is hydrogen or an ethyl group and, in particular, a 3,4-dichlorobenzyl or 3-phenylpropyl group, orstands for a group of the partial formula la wherein alk represents the trimethylene, 2- hydroxytrimethylene and, in particular, the ethylene radical, R represents hydrogen or a methyl or 'benzyl group, and R}, represents hydrogen or a methyl group, or R and R together represent a tetramethylene, pentamethylene or 2,2-(1,4-methanopentamethylene)- pentamethylene group and, in particular, a 2,2- pentamethylene-pentamethylenc group which forms, together with the adjacent nitrogen atom, the 2-azaspiro[5.5]un dec-2-yl radical. The antiviral activity of compounds of the general formula'l and of their acid addition salti, such as (lRS,2RS,4SR)- spiro[norbornan=2,3'-piperidine]=hytirochloride, 1'-

(3,4-dichlorobenzyl IRS.2RS,4SR) spiro[norbornane-2.3-piperidinel-hydrochloride. l- (3-phenylpropyl)-( lRS.2RS.4SR)-spiro[norbornane 2.3-piperidine]-hydrochloride and l '-[2-.( 2- azaspiro[5.5]undec-2-yl)-ethyl]-spiro[bicyclo[ 2.2.2] octane-2.3-piperidinel-dihydrochloride. was determined. for example. on rhino-viruses (grown in biocytocultures) of the strains Type' 2 (HGP). Type 39 (209). TypeSl (F0 1) and others. Furthermore. compounds of the general formula I and their acid addition salts also exhibit antiviral activity in the caseof RS- viruses. influenZa-A2-viruses and adeno-viruses.

The antiviral activity of the compounds of the general formula I and of their pharmaceutically acceptable acid addition salts. as well as the favourable therapeutic index. distinguishes these new substances as active substances that can be used for the prevention and treatment of virus infections of mammals, particularly of diseases of therespiratory tract, such as nasal catarrh, influenza and acute bronchitis.

The new compounds of the general formula I and their acid addition salts'are produced by a process in which a corresponding dicarboxylic acid imide of the general formula ll wherein R,. m and n have the meanings given'under formula I. is reduced by means of a complex hydride; and. optionally. the obtained compound of the general formula I converted into an addition salt with an inorganic or organic acid. A

The reduction of imides of the general formula ll is effected. for example, by means of lithium aluminium hydride or diborane in an ethereal solvent such as diethyl ether; tetrahydrofuran. dibutyl ether or diethylene glycol diethyl ether, or in "mixtures thereof. at temperatures ofbetween ca. 20 and 100C or the boiling temperature of the employed reaction medium. The diborane can either be separately produced and then introduced, or be formed in situ from sodium borohydride and borotrifluoride-etherate.

The imides of the general formula ll can be produced uent'; such'as. benzene. in a closed vessel and with a reaction time of ca. 'l6-36 hours, whereby approximately equimolar amounts of diene and dienophile are used. It is advantageous in some cases to employ, instead of an imide. a precursor thereof to serve as dienophile, and to form the optionally substituted imide example.'the aforementioned cyclic diene is firstly reacted with Z-methyleneglutaronitrile to give 2-cyano-5- norbornene'-2-propionitrile or 2-cyanobic'yclo[2.2.2loot-5-ene-2-propionitrile. By catalytic hydrogenation of the remaining double bond of these dinitriles. 'e.g. in the presence of platinum dioxide at room temperature and under 'normal pressure in a lower alkanol. and boiling of thehydrogenation product with cone. hydrochloric acid. there are obtained the imides embraced by the general formula ll wherein R, is a hydrogen atom. m denotes l and n denotes l or 2. Moreover. it is also possible. with the use of free methylehesuccinic acid or Z-methyle'neglutaric acid as dienophiles. to firstly produce the dicarboxylic acids on which the imides of the general formula [I are based. to convert these by boiling with acetic anhydride into their inner anhydrides, and to react the last-named with compounds of the general formula ll a,

H N R, (II :1) wherein R, has the meaning given under formula I. for example, in glacial acetic acid at its boiling temperature. to give imides of the general formula ll. Imides without N-substituent are obtained also by conversion of the aforementioned dicarboxylic acids into their diarnrnonium salts and heating of these until the release of ammonia and water is completed. Mentioned as a further possibility for the production of the dicarboxylic acids is also the hydrolysis'of the corresponding dinitriles, of whichsome have already been referred to above,,,with moderately concentrated sulphuric acid or with lower-alkanolic potassium hydroxide solution; and as a. further means of arriving at the corresponding anhydrides. their direct production by diene synthesis with the use of methylenesuccinic.acid'an hydride or 2-methylene-glutaric acid anhydride. In addition, im-' ides of the general formula II wherein R, is not hydrogen can be obtained also by reaction of alkali metal salts of the imides embraced by the general formula ll, and unsubstituted in the imide group, with reactive esters of compounds of the general formula Ill given below.

According to a second process. compounds of the general formula l wherein R, is not hydrogen are produced by the reaction of a compound of the general formula lb embraced by the general formula I:

jugc V g c I I NH (lb),

.1. H2). i 2Cv\l/C-H,

(Ill).

- with the exception 'of hyd'rogen',

group not until after the performed diene synthesis. .For

1n the presence ofa'an acid-binding agent, or'with formaldehyde: in the 'presence of formic acid; and, optionally, the conversion of the obtained compound embraced by the general formula I into an addition salt with an inorganic or organic acid. i

Suitable reactive esters of compounds of the general formula III are, for example, areneand alkanesulphonic acid esters, such as benzenesulphonic acid ester, p-bromobenzenesulphonic acid ester, p-toluenesulphonic acid ester or methanesulphonic acid ester, as well as, in particular, hydrohalic acid'esters, such as, e.g. bromides and chlorides; and also, as specific sulphuric acid esters, dimethylsulphate and diethylsulphate. An excess of the basic compound to be reacted of the general formula lb can serve as the reaction medium and, at the same time, as an acid-binding agent. The reaction is preferably performed, however, in an organic solvent. such as ethanol, butanone, dioxane or dimethylformamide, whereby, instead of excess com pound of the general formula lb, another acid-binding agent, e.g. a tertiary organic base such as, e.g. ethyldiisopropylamine, or, in particular, inorganic basic substances, such as, e.g. potassium or sodium carbonate. can be used for the binding of the liberated acid. Both the starting materials of the general formula lb, and the reactive esters of compounds of the general formula lll which contain an amino group as defined, can be used also in the form of their acid addition salts, from which the bases are liberated in situ by the corresponding amount of an acid-binding agent, such as, e.g. potassium carbonate. The reactions are performed preferably at temperatures of between ca. 50 and 180C and, depending on the boiling temperature of the employed ester and of the solvent, if necessary in a closed vessel. For the reaction with formaldehyde in the presence of formic acid, the procedure entails, for example. the heating of a compound of the general formula lb in a mixture of formaldehyde and formic acid for ca. k to 5 hours at temperatures of between ca. 70 and 100C.

The compounds of the general formula lb are, in their turn, preferably produced according to the firstmentioned process by the reduction of the corresponding imides of the general formula ll. Reactive esters of compounds of the general formula Ill are known in large numbers; others can be produced by methods analogous to those for the known ones.

According to a third process, compounds of the general formula I wherein R, is not hydrogen, as well as their acid addition salts, are obtained by the reduction, by means of a complex hydride, of a compound of the general formulalV wherein R, represents a radical lessened by a methylene group, but otherwise corresponding to the definition for R given under formula I. and m qand n have the meanings given under formula I, or ofa-compound of the general formula V t m and n each' 'represent 0 or 1 and have a sum always equal to l,

alk" represents a bivalent. saturated aliphatic hydro carbon having(2-"m) to (5-m') carbon atoms, and

R represents a radical lessened by the group (Cl-12),, but otherwise correspondingto the definition for R given under formula I, or. wherein n is 1, can represent a lower alkoxy group, and R m and 1 have the meanings given under formula l; and, optionally. the conversion of the obtained compound embraced by the general formula 1 into an addition salt with an inorganic or organic acid.

The reduction can be performed, for example, with lithium aluminium hydride or with diborane under the same conditions'as for the reduction of the dicarboxylic acid imides of the general formula ll. The starting materials of the general formula IV can be produced from compounds of the general formula lb by the usual methods; particularly by reaction with carboxylic acid halides or anhydrides in the presence, of tertiary organic bases, such as pyridine. Compounds of the gen eral formula IV of which the radical R," contains a primary, secondary and tertiary amino group are produced from the compounds of the general formula lb preferably in two steps, in that the stated compounds are firstly reacted with halogenalkanoyl halides having 2 to 5 carbon atoms to give corresponding N- halogenalkanoyl derivatives, and these allowed to react with a compound of the formula Vll given below or, if necessary, with an N-alkali metal derivative of such acompound.

Starting materials of the general formula V wherein m denotes l and n denotes O are obtained, for example, by reaction of compounds of the general formula lb with halogenalkaneam ides, such as, e.g.

the general formula V a R, CO OH wherein R represents a radical lessened by a methylene group, but otherwise corresponding to the definition for R or with lower chloroformic acid alkyl esters, in the presence of acid-binding agents. I

According to a fourth process, the compounds (embraced by the general formula I) of the general formula Ic given below and their acid addition salts are produced by the reaction ofa reactive ester ofa compound of the general formula VI wherein alk. m and n have the'ineanings given under formula I, with a compound of the general formula VII R (vii) wherein R and R have the meanings given under formula l. or with an alkali metalcompound of a secondary amine embraced by the general formula VII; and, optionally, theconversion of theobtained compound embraced by the general formula I into an addition'salt with an inorganfc or organic acid. The compounds obtained by this process correspond to the general-formula Ic 8, wherein alk, R R rri and n have the meanings given under formula I. I i

Suitable reactive esters of compounds of the general formula VI are, for example, sulphonic acid esters such as thep-toluenesulphonic acid ester and the methanesulphonic acid estenand, particularly hydrohalic acid esters such as, e.g. bromides and chlorides. An excess of the basic compound of the: general-formula VII to be reacted can serve as the reaction medium and at the same time, as the acid-binding agent. Provided that the reactive esters to be reacted are based on compounds having :aprimary hydroxy group, the reaction can be carried-out in most cases already at temperatures between 50- and C. Depending on. the boiling temperatureof the compound of the general formula VII, the reaction is carried out if necessary in a closed vessel: It can also be..performed in a solvent such as, ethanol, butanone. dioxane or dimethylformamide, whereby for the binding of the liberated acid it is possible to use, instead of excess compound of the general formula VII, also tertiary organic bases such as, for example, ethyl-diisopropylamine. or inorganic basic substances such as, for example, sodium and potassium carbonate. In the case of reactions of reactive esters of compounds of the general formula VI of which the hydroxy group is not primary-bound with amines of the general formula VII, higher temperatures of between ca. 100 and C are in most cases necessary, and with the use of ammonia or low-boiling amines and/or the use of low-boiling solvents, closed vessels required. The N-alkalimetal compounds, which can optionally be used instead of the free secondary amines, are, for example, formed in situ e.g. by reaction withsodium amide, sodium hydride or lithium amide, in an inert organic solvent, such as, e.g. benzene or toluene, and subsequentlydirectly reacted.

The compounds of the general formula VI in their turn are-produced, for example, by reaction of com-' pounds of the general formula Ib with halogenalkan ols having 2 to 5 carbon atoms in the presence of acidbinding agents, such as potassium carbonate ortriethylamine. in ethanol' at the boiling temperature,'analogously to the secondmentioned process for the production of compounds of the general formula I, or moreover by reaction of compounds of the general formula lb with vic. epoxyalkanes' hav'ing2 to 5 carbon atoms, such as, e.g: ethylene oxide. The reactive esters required as direct starting materials can beproduced' from the compounds of the general formula VI, e.g. by reaction with thionyl chloride, phosphorus tribromide, p-toluenesulphochloride or methanesulphochloride; it is also possible, however, to react compounds of the general formula Ib direct with equimolar amounts of bis-halogenalkanes or p-toluenesulphonic acid halogenalkyl esters, in the presence of acid-binding agents, to give the corresponding N-halogenalkyl compounds as reactive esters of compounds of the general formula VI.

Compounds of the general formula 10 (embraced by the general formula I) given above wherein R and R are hydrogen atoms, and their acid addition salts, can be produced by a fifth process comprising the reduction of a nitrile of the general formula VIII (Vllll wherein alk' represents a bivalent,v saturated aliphatic hydrocarbon radical having 1 to 4 carbon atoms,

and m and n have the meanings given under formula Y and, optionally, the conversion of the obtained compound embraced by the general formula I into an addition salt with an inorganic or organic acid. The nitriles of the general formula Vlll can be reduced by chemical methods, especially by means of complex hydrides, such as lithium aluminium hydride or diborane. in ethereal solvents, such as tetrahydrofuran or diethyl ether, at temperatures of between ca. 20 and 100C. Likewise suitable is catalytic hydrogenation. which is performed, e.g. in the presence of Raney nickel in an on ganic solvent, such as methanol or ethanol. at elevated temperature and under elevated pressure, e.g. at 50 to 100C and under ca. 100 to 200 bars, and preferably in the presence of ammonia. The nitriles of the general formula VIII can be produced, for example. by reaction of reactive esters of compounds of the general formula VI with potassium or sodium cyanide in the usual manner. w

The compounds of the general formula Ic given below and embraced by the general formula I. in which formulae R alk, m and n have the meanings defined under formula I, and R has the meaning given there with the exception of hydrogen, and their acid addition salts are produced according to a sixth process comprising the reaction of a compound of the general formula Id embracedby the general formula I 'uin.

in a molar ratio chosen to suit the number of hydrogen atoms to be replaced. or with formaldehyde in formic acid in an amount sufficient for the replacement of all the hydrogen atoms bound to the nitrogen atom of the side chain; and. optionally. the conversion of the obtained compound embfaced by the general formula I into an addition salt with an inorganic or organic acid. Types of reactive esters of compounds of the general formula [X which can be used are the types mentioned in the case of the second process for the production of compounds of the general formula I, with the same reaction conditions. acid-binding agents and solvents. The monoor dimethylation with formaldehyde and formic acid to form a tertiary amine embraced by the general formula Ic can be performed under the conditions given for the second process for the production of compounds of the general formula I.

Compounds of the general formula I wherein R represents an alkyl group substituted in the 2-position by a hydroxy group and optionally in another position by chlorine and: having at most 6 carbon atoms. or a 2- hydroxypropyl group substituted in the 3-position by the group NR R wherein R and R have the meaning given under formula I, and m and n have the meanings given under formula I. and their acid addition salts are produced according to a seventh process comprising the reaction of a compound of the general formula Ib given above. wherein m and n have the meanings given under formula I. with a compound of the general formula X wherein R represents hydrogen. an optionally chlorinesubstituted alkyl group having at most 4 carbon atoms, or a methyl group substituted by the group NR R wherein R and R have the meanings given under formula l, and

R represents hydrogen. or. if R is an alkyl group optionally substituted by chlorine. can represent an alkyl group'containing. together with R at most 4 carbon atoms; and, optionally, the conversion of the obtained compound embraced by the general formula I into an addition salt with an inorganic or organic acid.

The reaction according to the process is performed in the presence or absence of aninert organic solvent at temperatures from ca. 0C. preferably at room temperature or at moderately elevated temperature. On ac count of the exothermic reaction with the use of particularly reactive starting materials of the general formula X, cooling is to be applied where necessary. The application of the mildest possible conditions is particularly of importance if the radical R of the compound of the general formula X contains a chlorine atom'yotherwise the reaction can be carried out if necessaryals oat higher temperatures up toca. C. It is possible to use as'solvents, e.g. lower alkanolssuch asf'for example, ethanol or methanol, lower alkoxyalkanols such as 2-methoxyethanol, or ethers and ethereal solvents such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane; and the reaction canbeperformed if necessary in a closed vessel,

wherein R and R have the meanings given under formula I with potassium or sodium hydroxide, or'by reaction of N-alkali metal derivatives of amines of the general formula VII given above, particularly of cyclic compounds embraced by this formula I such as, e.g.

compounds of the earlier given'general forrnula lb wherein mand n have the meanings given under formula l. with epichlorohydrin l-chloro-2,3- epoxypropane) Some compounds of the general formula Xa are known, and further such compounds obtainable, e.g. analogously tothe above-mentioned process for the production of compounds of the general formula I by reaction of epichlorhydrin with amines of the earlier given general formula VII.

The present invention comprises also such modifications of the above mentioned processes, as well as of the preceding steps mentioned subsequent to these, where a process is interrupted at a particular stage, or where a compound occurring as an intermediate at a certain stage is taken as the starting material and the uncompleted stages performed, or where a starting material is formed under the reaction conditions or is'optionally usedin the form ofa salt. The required starting materials can be used either as racemates or as isolated optical antipodes. Instead of using specific racemates, it is also possible to use, where advantageous; e.g. if the conditions for separation into individual racemates and. if desired, into individual optically active antipodes'in the case of the final materials are more favourable than in the case ofthe starting materialsor intermediates thereof, mixtures of racemates. Such starting materials too can be optionally used in the form of salts.

The new heterocyclic spiro compounds of the. general formula I obtained by the process according to the invention. are optionally converted, in the usual manner. into their addition salts with inorganic and organic acids. For example, the acid,or a solution thereof, desired as the saltcomponent is added to a solution of a compound of the general formula I in an organic solvent, such as diethyl ether, acetone, dioxane, methanol or ethanol; ahd the' salt, which has precipitated directly "or after addition of a second organic liquid such as, e.g.

diethyl e'lihei to methanol or acetone, separated.

Administration of the new heterocyclic spiro compounds 'of the general formula I and their pharmaceuti- Cally acceptable acid addition salts can be effected, in dosage units appropriate for the purpose, particularly orally, rec tally or parenterally, for example, intramuscularly or intravenously, or locally, especially by way of the mucous lining of nose, mouth and throat, or by way of the respiratory tracts. In general, the free bases are applied in daily doses of 0.1 10 mg per kg of body Weight; the dosage however in the case of local adminis tration can optionally be appreciably lower, The same dosage amounts apply also to the pharmaceutically acceptable acid addition salts of the heterocyclic spiro compounds of the general formula I; but where the acid component constitutes a considerable part of the total active substance the doses are optionally increased accordingly.

Suitable active substances of antiviral pharmaceutical preparations according to the invention are, besides the free bases of the general formula I, e.g. their addition salts with hydrochloric acid, hydrobromic acid. sulphuric acid, phosphoric acid. methanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, acetic acid, lactic acid, succinic acid, fumaric acid. maleic acid,'malic acid. tartaric acid, citric acid, benzoic acid, salicyclic acid, phenylacetic acid, mandelic acid and embonic a c'idj Suitable dosage units, such as drageesitablets, capsules, suppositories or ampoules, contain as active substance l-lOO mg, preferably 5-50 mg ofa heterocyclic spiro compound of the general formula I or of a pharmaceutically acceptable acid addition salt thereof. A further possibility is the application of suitable amounts of preparations not administered as dosage units, such as syrups, sprays, tinctures, aerosols, ointment s orpowders. I

'The'content of active substance in dosage units' for oral administration is preferably between l0% and Such dosage units are prepared by the combination of the active substance with, for example, solid pulverule'nt carriers, such as lactose, saccharose, sorbito'l, manni tol starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or dragee cores. The dragee cores are coated with, for example, concentrated sugar solutions which may also contain, e.g. gum arabic,.talcum and/or tita- 'niufn dioxide; or with a lacquer'dissolved in readily volatile organic solvents or solvent mixtures. Dyestuff can be added to these coatings in order, for' example, to facilitate identification of the various doses of active substance. Further suitable oral dosage units are hard capsule's made from gelatine, as'well as soft closed capsules made from gelatine and a softener such as glycerin. The hard capsules contain the active substance preferably as a granulate in admixture with lubricants such as talicum or magnesium stearate; and optionally stabilisers such as sodium metabisulphite (Na,s,o,) or ascorbic acid. The active substance in soft capsules is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, to which likewise stabilisers mayjbe added.

Suitable dosage units for rectal administration are,

for example, suppositories consisting of a combination of an active substance with a suppository foundation substance based on natural or synthetic triglycerides '(e,g'. cocoa butter), polyethylene glycols or suitable higher fatty alcohols; and gelatine rectal capsules containing a combination of the active substance with polyethylene glycols.

Ampoule solutions for parenteral administration, es-

-pecially intramuscular or intravenous administration,

contain, for example, a compound of the general formula l in a concentration preferably of 0.5 as an aqueous dispersion prepared with the aid of the usual solubility-promoting agents and/or emulsifiers, as well as optionally stabilising agents; or preferably an aqueous solution of a pharmaceutically acceptable. watersoluble acid addition salt of a compound of the general formula I.

For liquids for oral administration, such as syrups and elixiers, the concentration of the active substance is so adjusted that a single dose can be easily measured out, eg as the content of a tea-spoon or of a measuringspoon, e.g. 5 ml, or as a multiple of these volumetric amounts. Suitable as syrups are, for example, solutions of water-soluble acid addition salts, or suspensions of insoluble but absorbable acid addition salts. in aqueous solutions of sugars and/or alkane polyols, such as unrefined sugar or sorbitol or glycerin, flavourings and aromatics, as well as optionally preservatives and stabilisers. Elixiers are aqueous-alcoholic solutions of a compound of the general formula I or of pharmaceutically acceptable salts thereof, which likewise may contain the additives mentioned in the case of the syrups. Further oral preparations which may be mentioned are dropping solutions, which in most cases contain a fairly high alcohol content and, at the same time, a fairly high active-substance content, so that a single dose can be measured out, for example, as to 50 drops.

The following examples (a) to (g) are to illustrate the production of some typical preparations, but these do not in any way represent the only forms of such preparations. In place of the given active substances contained therein, others may also be used. e.g. the further compounds of the general formula I described in the examples, particularly in the form of their acid addition salts.

a. An amount of 250.0 g (azaspiro[5.5]undec-2-yl)-ethyl]- spiro[bicyclo[2.2.2]octane-2,3'-piperidine]dihydrochloride is mixed with 550 g of lactose and 292.0 g of potato starch; the mixture is moistened with an alcoholic solution of 8 g of gelatine, and granulated through a sieve. The obtained granulate is dried and additions are then made to it of 60.0 g of potato starch, 60.0 g of talcum, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide; the mixture is pressed to form 10,000 tablets each weighing 125 mg and each containing mg of active substance; if desired, these can be provided with grooves to facilitate a more precise adjustment of the dosage amount.

b. A granulate is produced from 250.0 g of lRS.2R- S,4SR)-spiro[norbornane-2,3'-piperidine]- hydrochloride, 379.0 g of lactose and the alcoholic solution of 6.0 g of gelatine; the said granulate is then dried and additions are made to it of 10.0 g of colloidal silicon dioxide, 40.0 g of talcum, 60.0 g of potato starch and 5.0g of magnesium stearate; the mixture is subsequently pressed to form 10,000 dragee cores. These are afterwards coated with a concentrated syrup made from 533.5 g of crystallised saccharose, 20.0 g of shellac, 75.0 g of gum arabic, 250.0 g of talcum, 20.0 g of colloidal silicon dioxide and 1.5 g of dyestu-ff; the coated dragees are finally dried. The obtained dragees each weight 165 mg and each contain 25 mg of active substance.

c. An amount of 20.0 g of (IRS,2RS,4SR)- spiro[norbornane-2,3-piperidinel-hydrochloride is dissolved in 1500 ml of boiled, pyrogcn-free water, and

the solution made up with such water to 2000 ml. The solution is filtered off. filled into 1000 ampoules each of 2 ml, and then sterilised. A 2 ml ampoule contains 20 mg or 1.071 of active substance.

d. 25 g of 1'-[2-(2-azaspiro[5.5]undec-2-yl)-ethyl]- spiro [bicyclol2.2.2]octane-2,3-piperidine]- dihydrochloride and 1975 g of finely ground suppository foundation substance (e.g. cocoa butter) are thoroughly mixed and then melted. There are obtained from the melt. maintained homogeneous by stirring. 1000 suppositories each weighing 2.0 g and each containing 25 mg of active substance. e.

e. For the obtainment of a syrup containing 0.25% of active substance. a solution is prepared of 1.5 liters of glycerin, 42 g of hydroxybenzoic acid methyl ester. 18 g of p-hydroxybenzoic acid-n-propyl ester and, with gentle heating. 25.0 g of (lRS,2RS.4SR) spiro[norbornane2.3piperidinel-hydrochloride in 3 liters of distilled water; additions are then made of4 liters of 7071 sorbitol solution. 1000 g of crystallised saccharose. 350 g of glucose and an aromatic. eg 250 g ofOrange Peel Soluble Fluid of Eli Lilly and Co.. lndianapolis, or in each case 5 g of natural lemon aroma and 5 g of Halb und Halb"-essence. both from the firm Haarmann und Reimer. Holzminden, Germany; the obtained solution is filtered and the filtrate subsequently made up to 10 liters with destilled water.

f. For the preparation of a dropping solution containing 1.5% of active substance. 150.0 g of (lRS,2RS.4SR)- Spiro[norbornane-2.3'piperidinel-hydrochloride and 30 g of sodium cyclamate are dissolved in a mixture of 4 liters of ethanol (96%) and 1 liter of propylene glycol. A mixture is prepared of 3.5 liters of sorbitol solution with 1- liter of water, and this mixture then added to the above active-substance solution. An aromatic is subsequently added. e.g. 5 g of cough-lozenge aroma or 30 g of gfrapefruit essence, both from the firm of Haarmann und' Reimer. Holzminden. Germany, the whole well mixed. filtered. and made up to 10 liters with distilled water.

g. For the preparation of a'nasal spray containing 0.1% of active substance. an amount of 10.0 g of 1'-[ 2-(2-azaspiro[ 5.5 lundec-Z-yl )-ethyl ]-spirolbicyclo [2.2.2]octan-2,3'-piperidine]-dihydrochloride is dissolved in 10 liters of distilled water. and the solution filled into spray-bottles. For the prevention and treatment of the cold in the head, 2-3 spurts from a full bottle (from a partially emptied bottle more if necessary) are injected. e.g. once to three times daily. into each nostril.

The following examples illustrate the production of the new heterocyclic spiro compounds of the general formula 1, as well as of new starting materials; but these examples are notmeant in any way to restrict the scope of the invention. The temperatures are expressed in degrees Centigrade.

Example 1 An amount of 50 g (0.24 mole) of spirolbicyc1o[2.2.2]octane-2,3'-piperidine]2, 6-dione is introduced portionwise by means of a connecting tube in the course of 15-20 minutes, with stirring. into a mixture of 14 g (0.37 mole) of lithium aluminium hydride in 3 liters of abs. ether. The temperature during the addition is not to exceed 25. The mixture is refluxed under nitrogen for 32 hours. After subsequent cooling, successive additions are'rnad-e'dro pwise of 14ml of'water, 28 ml of 2N sodium hydroxide'soluti'on and afu rther 28 ml of water. The mixture is then stirred for 1 hour; it is afterwards filtered under reduced pressure and the residue subsequently well washed with ether. The filtrate is dried over sodium sulphate and concentratedby evaporation. The'residu'e is fractionated inhig h vacuum to obtain 'spiro[bicyclo '[2.2.2]octane- 2.3'- piperidine], B.P. 95130/0.2 Torr. From this base there is obtained, with excess ethereal hydrogen chloride solution, spiro[bicyclo]2.2.2loctane- 2,3-piperidinel-hydrochloride, N.P. 207-208 .5 (from acetone/ether).

The spiro[bicyclo[2.2'.2]octane-2,3'-piperidine]-2, 6'-dione serving as starting material is produced as follows:

a. A mixture of 150 g (1.88 moles) of 1,3- cyclohexadiene, 203 g (1.88' moles) of 2- methyleneglutaronitrile and 1.9 g (0.02 mole) of hydroquinone is heated in a pressure autoclave, with stirring and under a maximum pressure of bars. for hours at 'l50. The dark brown resin obtained after cooling'is rinsed with methylene chloride in a distilling flask and the solvent evaporated off. The residue is fractionated under high vacuum to obtain a sterioisomeric mixture of Z-cyanobicyclo[2.2.2]oct-5-ene-2-propionitrile, B.P.

b. An amount of 128.7 g (0.69 mole) of 2- cyanobicyclo]2.2.2]oct-5-ene-2-propionitrile is dissolved in-1.3 liters of the purest methanol; an addition is then made of 3 g of palladium charcoal (5% Pd) and hydrogenation performed at 15-25 under normal pressure to effect a hydrogen absorption of 90% of theory. After removal by filtration of the catalyst, the solvent is evaporated off and the residue fractionated to obtain 2-cyano-bicyclo [2.2.2]octane-2-propionitrile, B.P. 1 141 16/0.01 Torr.

c. 105.2 g (0.56 mole) of 2-cyano-bicyclo[2.2.2]oc tane-Z-propionitrile is mixed with 1600 ml of con'c. hydrochloric acid, and the mixture refluxed in a preheated oil bath, with stirring, for 10 minutes. The white precipitate, which has already formed before expiration of this period of time, is filtered off after cooling of the'mixt ure, and the filter residue washed with water until neutral. After drying in a desiccator over phosphorus pentoxide, the white crystals are Sublimated at l70/0.l Torr to obtain spiro[bicyclo[2.2.2]octane- 2,3-piperidine]-2,6-dione. M.P. 183184.

Example 2 a. 426 g (4 moles) of 2-methyleneglutaronitrile, 264

g (4 moles) of cyclopentadiene, 4 gof hydroquinone and 500 ml of benzene are heated in a pressurea utoclave at 160 and under a ma'ximum pressure of 3 bars, with stirring, for 10 hours. The mixture obtained after cooling isconcentrated'in vacuo (ca. 12 Torr), the residue twice extracted with 1.5 liters of petroleum ether each time and then extracted in high vacuum. The crude product is obtained as colourless oil. B.P. i 1 51 28"/0.03 Torr. which is dissolved in 300 ml of ethanol. On storage of this solution in a refrigerator overnight, there crystallises 2-exo-cyano-5- norbornene-2-endo-propionitrile. M.P. 40-42.

b. An amount of 200 g (1116 moles) of 2-exo-cyano'5-norbornene-2 endo-propionitrile is hydrogenatedan alogously to Example 1 b) to obtain 2- exo-cyano-norbornane-Z endo-propionitrile. B.P. l20-128/O.1 Torr.

c. 52.2 g (0.30 mole) of 2-exo-cyano-norbornane-2- endo-propionitrile. is refluxed. analogously to Example 10). with cone. hydrochloric acid, whereupon (1RS,2- RS,4SR)-s piro[norbornanev 2,3'-pip eridine]-2',6'-dione, tained.

154-156 is ob- Example 3 An amount of 14.3 g (0.08 mole) of 1RS,2RS,4SR)- spiro[norbornane2,3'-pyrrolidine-2',, 5'-dione] is reduced, by a procedure analogous to that described in Example 1, with 4.56 g (0.12'r'nole) of lithium aluminium hydride in 400 ml'of tetrahydrofuran to obtain (1- R S,2RS,4SR)-spiro[norborn ane-2,3-pyrrolidine, B.P. -102/12 Torr. The base is converted with etheral hydrogen chloride solution into (1RS,2RS,4SR)-spiro [norbornane-2,3-pyrrolidine] hydrochloride, M.P. 200 202. t

The starting'material is produced as follows:

a. 650 g (5 moles) of methylenesuccinic acid (itaconic acid) and 1 g (0.0091 mole) of hydroquinone are dissolved in a mixture of 1000 ml of isopropanol and 1000 ml of water, and, with vigorous stirring, 395 g of cyclopentadiene added within 1 hour. The mixture heats up and the rate of addition must be reduced if the reaction becomes too violent. The reaction mixture is then refluxed for 7 hours with stirring and afterwards completely concentrated by evaporation. The water is removed by the residue being concentrated by evaporation three times with ethanol and twicewith benzene, whereupon crude 2 -carboxy-5-norbornene-2-acetic acid is obtained as an epimer mixture. Y

b. An amount of 257 g (1.31 moles) of crude 2 carboxy-5-norb'o'rnene-Z-acetic acid mixture is dissolved in 1500 ml of benzene and the solution boiled in a water-separator until there is no further separation of water (ca. 20 ml). Additions are then made of 500 ml of abs. ethanol and 3 g of p-toluenesulphonic acid, and the liberated water removed by azeotropic distillation. (A one-meter longsilver-coated column isolated with a vacuum-jacket and filled with glass spirals is required: otherwise no equilibrium can be established in the column.) After 48 hours no further aqueous phase can be separated in the water-separator. The cooled reaction mixture is poured on 500 mlof saturated sodium bicarbonate solution; and after thorough shaking the aqueous phase separated. The benzene extract is washed twice with 500 m1 ofisaturated sodium chloride solution each time. The aqueous phases are separately washed twice with 500 ml of benzene each time. The' -carboxy 5-norbornene-2-aceti c acid ethyl ester as an epimeric mixture.

c. 5.0g (0.0224 mole) ofa 2-carboxy-5-norbornene- 2-accitic acid/ethyl ester mixture suspended in 10 ml of water and an addition then made at 5, with stirring. of cone. sodium hydroxide solution until a phenolphthaleinalkaline reaction is obtained. There is subsequently added, likewise at 05, 1 g of sodium bicar bonate. and the mixture stirred until the sodium bicarbonate has gone into solution. A solution of 9.5 g (0.075 gram atom) of iodine and 9.1 g (0.055 mole) of potassium iodide in 30 ml of water is then added at -10, and the reaction mixture stirred for 1 hour at room temperature. Solid sodium bisulphite is now added portionwise, whereupon the initially dark mixture becomes colourless. There is subsequently added to the mixture sodium bisulphate until no further carbon dioxide is given off. Extraction is performed three times with 50 ml of methylene chloride each time, and the methylene chloride extracts are separately washed with in each case 50 ml of sodium bisulphite solution and a saturated sodium bicarbonate solution and with 50 ml of water. After drying over sodium sulphate, the organic phase is concentrated in vacuo (ca. 12 Torr) to obtain 2-endo-carboxy- 5-exo-iodo-6-endo-hydroxy-2-exo-norbornaneacetic acid ethyl ester, M.P. 103 104 (from ether). The aqueous phases are washed together, acidified with cone. hydrochloric acid, and extracted three times with 200 ml of methylene chloride each time. The methylene chloride extracts are washed separately twice with 50 ml of water each time, dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). There is thus obtained, as a second reaction product, crude 2-exocarboxy-5-norbornene-2-endo-acetic acid ethyl ester.

(1. An amount of5 g (0.023 mole of 2-exo-carboxy-5- norbornene-Z-endo-acetic acid ethyl ester is added to a solution of5 g of sodium hydroxide in ml of water and 100 ml of ethanol, and the mixture stirred for 16 hours at room temperature. The reaction mixture is afterwards concentrated in vacuo (ca. 12 Torr). The residue is dissolved in 50 ml of water and the aqueous solution extracted three times with 50 ml of methylene chloride each time. The methylene chloride extracts are extracted twice with 50 ml of water each time and subsequently discarded. The aqueous phases are combined, acidified with cone. hydrochloric acid, and extracted three times with 100 ml of methylene chloride each time. The methylene chloride extracts are washed separately with saturated sodium chloride solution and concentrated by evaporation to obtain 2-exo-carboxy- 5-norbornene-2-endoacetic acid, M.P. 152 (from water).

e. An amount of 6.0 g (0.0305 mole) of 2-exo-carboxy-5 norbornene-Z-endo-acetic acid is dissolved in 120 ml of the purest methanol; there is then added 300 mg of palladium charcoal (5% Pd) and hydrogenation performed at 2032 under normal pressure until a hydrogen absorption of 100% of theory is effected. After the catalyst has been filtered off, the solvent is evaporated off and the residue dried in vacuo (ca. 12 Torr) to obtain 2-exo-carboxy-2-endonorbornaneacetic acid, M.P. 145. 7 i

f. 5.83 g (0.0294 mole) of 2-exo-carboxy-2-endonorbornaneacetic acid is dissolved in 3 l .Zrnl of who ammonia, and the solution concentrated in'vacuo (ca. 12 Torr). The dry residue is heated for 1 hour at 200, during which time a large amount of ammonia is'given off.

' After this period of time, the evolution of gas ceases and the reaction is finished. The cooled residue is dissolved in 50 ml of methylene chloride and the obtained solution extracted twice with 50 ml of saturated sodium bicarbonate solution each time. The aqueous extracts were washed separately twice with in each case 50 ml of methylene chloride. The organic phases are combined, dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr) to obtain (lRS.2RS.4SR)-spiro[- norbornane-2,3'-pyrrolidine-2,5'-dione]. M.P. 168170 (from water).

Example 4 14.3 g (0.08 mole) of 1RS,2SR,4SR)-spiro[norbornane-2,3-pyrrolidine-2, 5-dione] is reduced with 4.56 g (0.12 mole) oflithium aluminium hydride in 400 ml of tetrahydrofuran analogously to Example 1. whereby (1RS,2SR.4SR )-spiro[norbornane-2,3 pyrrolidine], B.P. -105/l5 Torr is obtained.

The base is converted with ethereal hydrogen chloride solution into (1RS,2SR,4SR)-spiro[norbornane- 2,3-pyrrolidinel-hydrochloride-hydrate. M.P. 107-l08 (from benzene/ether).

The starting material is produced as follows:

a. An amount of 5.0 g (0.0143 mole) of Z-endocarboxy- 5-ex0-iodo-6-endo-hydroxy2-exo-norbornaneacetic acid ethyl ester (first reaction product of Example 3c) is dissolved in 168 m1 of glacial acetic acid; there is then added portionwise to the solution at 10-15, within 10 minutes, 7 g of superpure zinc powder. The mixture is filtered and the filtrate concentrated in vacuo (ca 12 Torr). The residue is suspended in 50 ml of saturated sodium bicarbonate solution, and the suspension extracted three times with 50 ml of methylene chloride each time. The methylene chloride extracts are separately extracted once in each case with 50 ml of saturated sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation: there is thus obtained a neutral product which was subjected to no further investigation. The aqueous phases are combined. washed with methylene chloride, acidifiedwit'h conc. hydrochloric acid, and extracted three times with 100 ml of methylene chloride each time. The methylene chloride extracts are each washed twice with water, dried over sodium sulphate. and concentrated by evaporation to obtain crude 2 endocarboxy-5-norbornene-2-exo-acetic acid ethyl ester.

b. There is obtained, analogously to Example 3d, 2- endocarboxy-S-norbornene 2 exo-acetic acid, M.P. l61l62, starting with 30 g (0.134 mole) of 2-endo-carboxy-S-norbornene-2-exo-acetic acid ethyl ester and 16 g of sodium hydroxide.

c. There is obtained. analogously to Example 3e), 2- endocarboxy-2-exo-norbornaneacetic acid, M.P. l47-157, starting with 30 (0.153 mole) of 2-endo-carboxy-5-norbornene-2-exo-acetic acid in the presence of 1.5 g of palladium charcoal (5% Pd) after a hydrogen absorption of 99% of theory.

d. There is obtained, analogously to Example 3f, (1 R- S,2SR.4SR)-spiro[2',3'-pyrrolidine-2',5-dione], M.P. 145-146 (from water), starting with 30 g (0.151 mole) of 2-endo-carboxy-2-exo-norbornaneacetic acid and m1 of cone. ammonia.

EXAMPLE 5 An amount of 6.0 g (0.030 mole) of spiro[bicyclo[2.2.2]-octane-2,3-piperidine] is dissolved in 50 ml of ethanol; additions are then made of 6.8 g (0.033 mole) of phenethylbromide and 10 g (ca. 0.07 mole) of anhydrous potassium carbonate. and the whole subsequently refluxed, with stirring. for 18 hours. The reaction mixture is filtered. and the brown filtrate concentrated in vacuo (ca. 12 Torr). The viscous residue is distributed between 100 ml of methylene chloride and 100 ml of water. The methylene chloride phase is separated. and the aqueous phase afterwards washed twice with 100 ml of methylene chloride. The combined methylene chloride solutions are dried over sodium sulphate. and then concentrated in vacuo (ca. 12 Torr). There is obtained viscous 1-phenethylspiro [bicyclo[2.2.2Joctane-2.2-piperidine]. This is dissolved in 50 ml of ether and there is then added to the solution, with stirring. 10 ml of saturated ethereal hydrogen chloride solution. The precipitated hydrochloride is filtered off. There is obtained, after recrystallisation from acetone. 1-phenethyl-spiro[2.2.2loctane- 2,3-piperidinel-hydrochloride, M.P. 263 (with decomposition).

There is obtained in an analogous manner 1'-benzylspiro[bicyclo[2.2.2]octane-2,3-piperidine] and its hydrochloride. M.P. 195.5197 (from acetone), starting with 6.0 g (0.034 mole) of spirolbicyclo[2.2.2]octane- 2.3'-piperidine]. 6.4 g (0.037 mole) of benzyl bromide and 10 g (ca. 0.07 mole) of anhydrous potassium carbonate.

EXAMPLE 6 There is obtained. analogously to Example 5, lethyl-( lRS,2RS.4SR )-spiro[norbornane-2.3 piperidinel-hydrochloride. M.P. 254257, starting with g (0.030 mole) of( 1RS.2RS.4SR)-spiro[norbornane-2.3-piperidine]-5 g (0.046 mole) of ethyl bromide and 10 g (ca. 0.07 mole) of anhydrous potassium carbonate.

The following are obtained likewise analogously to Example 5:

1-benzyl-( lRS.2RS.4SR )-spiro[norbornane-2.3 piperidineland its hydrochloride. M.P. 201-204 (from methanol/ether). starting with 4.8 g (0.029 mole) of (1RS.2RS,4SR)- spiro[norbornane-2,3'-piperidine]. 6.4 g (0.037 mole) of benzyl bromide and 5.5 g (ca. 0.04 mole) of anhydrous potassium carbonate;

1-(2-allyl)-(1RS.2RS,4SR)- spiro[norbornane-2.3'- piperidine] and its hydrochloride. M.P. 246-247 (from methanol/ether). starting with 6.4 g (0.039 mole) of 1RS.2RS,4SR )-spiro[norbornane- 2.3'-piperidine], 3.4 g (0.044 mole) of allyl chloride and 6.2 g (ca. 0.045 mole) of anhydrous potassium carbonate;

1-isopropyl-( l RS.2RS,4SR)-spiro[norbornane-2.3'- piperidine] and its hydrochloride, M.P. l87l90 (from methanol/ether), starting with 6.4 g (0.039 mole) of (lRS,2RS,4SR)-spiro[norbornane- 2,3'-piperidine], 5.4 g (0.044 mole) of isopropyl bromide and 6.2 g (ca. 0.045 mole) of anhydrous potassium carbonate;

1'-(3-phenylpropyl)-(1RS,2RS,4SR)-spiro[norbornane-2,3-piperidine] and its hydrochloride, M.P. 227-228 (from methanol/ether). starting with 6.4 g (0.039 mole) of (lRS,2RS,4SR)spiro[norbornane- 2,3'-piperidine], 8.8 g (0.044 mole) of 3-phenylpropyl bromide and 6.2 g (ca. 0.045 mole) of anhydrous p0- tassium carbonate;

EXAMPLE 7 2.93 g (0.0177 mole) of (1RS,2RS.4SR)-spiro[norbornane-2.3-piperidine]. 3.65 g (0.019? mole) of a-methylbenzyl bromide and 3.43 g of diisopropylethylamine are dissolved in 60 ml of benzene. and the solution stirred for ca. 14 hours at room temperature. The reaction mixture is then washed six times with water, and the aqueous phases in each case separately extracted with 50 ml of ether each time. The combined" organic phases are dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). The base remaining is dissolved in ether and an addition made to the solution, with stirring. of 6 ml of saturated ethereal hydrogen chloride solution. The precipitated hydrochloride is filtered off and recrystallised from acetone to obtain 1'-(a-methylbenzyl)-( lRS.2RS,4SR)-spiro[norbornane-2.3'-piperidine] hydrochloride-hemihydrate, M.P. 198-200.

EXAMPLE 8 An amount of 5 g (0.030 mole) of (1RS,2Rs,4SR)- sprio[norbornane-2,3-piperidine] is dissolved in a mixture of 4.15 g (0.09 mole) of formic acid and 30 ml (ca. 0.4 mole) of 35% aqueous formaldehyde solution, and the solution stirred for 14 hours at After cooling. the mixture is rendered alkaline with 50 ml of 207r sodium hydroxide solution. and extracted three times with 50 ml of ether each time. The ether extractsfare separately washed twice with in each case saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr).

,The residue is converted, analogously to Example 4, iiito the fumarate. There is obtained 1'-methyll.RS,2RS.4SR)-spiro[norb0rnane-2,3'-piperidine]- fumarate (1:1), M.P. 184-187.

EXAMPLE 9 Ani'amount of 8.9 g (0.03362 mole) of 1'-[2- (dimthylamino)- acetyl]-spiro[bicyc1o[2.2.2]octane-2,3'-piperidine] is dissolved in 300 ml of abs. ether; the solution is then added-dropwise in the course of 10 minutes, with stirring, to a mixture of 2.6 g (0.0685 mole) oflithium aluminium hydride in 100 ml of abs. ether. After completed addition, the mixture is refluxed under nitrogen for ca. 14 hours. There are then made to the mixture, cooled with ice water, successive additions dropwise of 2.6 m1 of water, 5.2 ml of 2N sodium hydroxide solution and 5.2 ml of water. After subsequent stirring for -1 hour, the mixture is filtered under reduced pressure,

and the filter residue afterwards thoroughly washed with ether. The filtrate is dried over sodium sulphate and then concentrated in vacuo (ca. v1 2 Torr). The residue is dissolved in 50 ml of abs. benzene and this solution again concentrated by evaporation. This procedure is repeated twice to effect removal of residual traces of moisture; there is thus obtained crude 1'-[2- (dimethylamino)-ethyl]-spiro[bicyclo[2.2.2]octane- I 2,3'piperidine]. There is then added excess ethereal hydrogen chloride solution to obtain 1"[2- (dimethylamino)-ethyl]-spiro[bicyclo[2.2.2]octane- 2"-piperidine]dihydrochloride, M. P. 295 (with decomposition).

The following are obtained in an analogous manner: 1-(2-piperidinoethyl)-spiro[bicyclo[2.2.2]octane- 2,3'-piperidine[-dihydrochloride, M.P. 280 (from methanol/ether), starting with 9.4 g (0.0309 mole) of l- (2-piperidinoacetyl)-spiro[bicyclo[2.2.2]octane- 2,3piperidine] and 2.4 g (0.0632 mole) of lithium aluminium hydride; 1-[ 2-( l-pyrrolidinyl)-ethyl spiro[bicyclo[2.2.2]octane-2,3'-piperidine] and its dihydrochloride, M.P. 300305 (from methanol/ether), starting with 6.8 g (0.0241 mole) of 1"-[2-(1 pyrrolidinyl)-acetyl]-spiro[bicyclo[2.2.2]octane-2,3'- piperidine] and 1.9 g (0.05 mole) oflithium aluminium hydride; 1'-[ 2-(benzylmethylamino)-ethyl spiro[bicyclo[2.2.2]octane-2,3'-piperidine] and its dihydrochloride, M.P. 275280 (from methanol/ether), starting with 12 g (0.0357 mole) of l-[2- (benzylmethylamino)-acetyl]-spiro[bicyclo[2.2.2]octane-2,3-piperidine] and 2.8 g. (0.0737 mole) of lithium aluminium hydride.

The 1'-[2-(dimethylamino)-acetyl spiro[bicyclo[2.2.2]octane-2,3-piperidine] serving as starting material is produced as follows:

a. An amount of 20 g (0.244 mole) of sodium acetate and 18 g (0.100 mole) of spiro[bicyclo[2.2.2]octane- LIV-piperidine] is dissolved in 100 ml of water and 300 ml of acetone. A two-phase system is formed, to which is added dropwise at to 5 an amount of 10.2 ml (14.4 g, 0.13 mole) of chloroacetyl chloride. An addition is then made to the mixture, at 0 to 5, of 700 ml of water, whereupon the reaction product precipitates in flake form. Stirring is maintained for a further hour and the reaction product subsequently filtered off. After washing and then drying of the product over phosphorus pentoxide in a desiccator, there is obtained 1 '-chloracetyl-spir0[bicycl0 [2.2.2] octane- 2,3piperidine], M.P. 63 (with decomposition).

b. 8.8 g (0.034 mole) of 1-chloroacetylspiro[bicyclo[2.2.2]octane-2,3-piperidine] is dissolved in 60 ml of a solution of dimethylamine in benzene, and the solution stirred for ca. 14 hours at room temperature. The mixture is washed six times with water; the aqueous phases are in each case separately extracted twice with 50 ml of ether each time. The organic phases are dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). The crude 1-[2- (dimethylamino)-acetyl]-spiro[bicyclo[2.2.2]octane- 2,3-piperidine] is obtained as colourless oil.

Also the following starting materials are obtained analogously to (b):

1'-(2-piperidinoacetyl)-spiro[bicyclo[2.2.2 loctane- 2,3-piperidine] as a clear oil from 5.5 g (0.0216 mole) of l-chloroacetyl-spiro[bicyclo[ 2.2.2]octane-2,3 piperidine] and 2.9 g (0.034 mole) of piperidine;

1 '-[2-( l-pyrrolidinyl)-acetyl]- spiro[bicyclo[2.2.2]octane-2,3'-piperidine] as colourless oil, from 6.0 g (0.024 mole) l'-chloroacety|- spiro[bicyclo[2.2.2]octane-2,3-piperidine] and 6.8 g (0.096 mole) of pyrrolidine;

l-[2-( benzylmethylamino)-acetyl spiro[bicyclo[2.2.2]octane-2,2'-piperidine] as colourless oil. from 9.1 g (0.0357 mole) of 1-chlor0acetylspiro[bicyclo[2.2.2]octane-2,3-piperidine] and 12.1 g (0.10 mole) of benzylmethylamine.

EXAMPLE 10 There is obtained, analogously to Example 9, 1'-[2- (2-azaspiro[5.5]undec-2-yl)-ethyl]-' spiro[bicyclo[2.2.2.] octane-2,3'-piperidine]- dihydrochloride, M.P. 260270 (from thanol/ether), starting with 4.9 g (0.0132 mole) of l- [2-(2-azaspiro[5.5]undec-2-yl)-acetyl]- spiro[2.2.2]octane-2.3-piperidine] and 0.5 g (0.0632 mole) of lithium aluminium hydride.

The starting material is obtained as clear oil. analogously to Example 9 b), from 5.9 g (0.023 mole) of 1'- (chloroacetyl)-spiro[bicyclo[2.2.2]octane-2,3'- piperidine] and 3.5 g (0.023 mole) of 2-azaspiro[5.- 5]undecane (R. C. Schreyer, J. Amer. Chem. Soc. 74, 3194 (1952), with the addition of 5 ml of triethylamine as additional acid-binding agent instead of excess dimethylamine.

EXAMPLE 1 1 There are obtained, analogously to Example 9,

1' [3 (1RS,2RS,4SR)-spiro[norbornane2,3 -piperidin]-1-' yl)-propyl]-spiro[bicyclo[2.2.2]octane-2,3-piperidine and its dihydrochloride-hydrate, M.P. 290292 (from methanol/ether), starting with 7.1 g (0.0179 mole) of 1-[3-((1RS,2RS,4SR)-spiro[norbornane-2,3 piperidin]-1-yl)-propionyl]-spiro[bicyclo[2.2.2]octane-2 3'-piperidine] and 0.7 g (0.0179 mole) of lithium aluminium hydride.

The starting material is produced as follows:

a. An amount of 2.0 g (0.0112 mole) of spiro[bicyclo[2.2.2]octane-2,3'-piperidine] is added. with ice cooling and with stirring, to a suspension of 2.4 g of sodium acetate in 30 ml of acetone and 10 ml of water; there is then added dropwise to the formed mixture at 05 1.8 g (0.014 mole) of 3-chloropropionyl chloride. An addition is subsequently made to the mixture, at 0-5, of ml of water, whereupon the reaction product precipitates in liquid form. The mixture is extracted three times with 50 ml of methylene chloride each time. The methylene chloride extracts are washed separatelyin each case once with saturated sodium bicarbonate solution and twice with water; they are then dried over sodium sulphate and afterwards concentrated in vacuo (ca. 12 Torr) to obtain 1-(3-chloropropionyl)- spirolbicyclo[2.2.2]octane-2,3'-piperidine]. b. 4.8 g (0.178 mole) of l'-( 3-chloropropionyl)- spiro[bicyc1o[2.2.2]octane-2,3'-piperidine] is dissolved in 50 ml. of abs. benzene; an addition is then made of 3.0 g (0.018 mole) of (1RS,2RS,4SR)- spiro[norbornane-2,3piperidine] (see Example 2) and 3.5 g (0.0267 mole) of diisopropylethylamine, and the whole refluxed in a nitrogen atomosphere, with stirring, for 42 hours. The mixture is concentrated in vacuo under 12 Torr, and the residue distributed between 50 ml each of water and of chloroform. After separation of the chloroform extract, the aqueous phase is subsequently extracted again with 50 ml of mei chloroform. The chloroform extracts are washed separately twice with 50 ml of water each time; they are then dried over sodium sulphate and concentrated in vacuo (ca. 12 Torr). There is thus obtained crude 1'- [3-(1RS,2RS,4Sr)-spiro[norbornane-2,3-piperidin]- 1-y1)-propionyl]-spiro[bicyclo[2.2.2]octane-2,3'- piperidine as colourless oil.

EXAMPLE 12 There are obtained. analogously to Example 9, 1'-[3- (benzylmethylamino)- propyl]-spiro[2.2.2]octane-2,3-piperidine and its dihydrochloride-hydrate, M.P. 246248 (from methanol/ether), starting with 13.2 g (0.0372 mole) of 1- [3-(benzylmethylamino)-propiony1]- spiro[bicylo[2.2.2]octane-2,3-piperidine] and 1.4 g (0.036 mole) of lithium aluminium hydride.

a. The starting material: 1'-[3-(benzylmethylamino)- propionyl]-spiro[bicyclo[2.2.2]octane-2,3'- piperidine], is obtained as clear oil, analogously to Example 11b), from 1.0 g (0.0372 mole) of 1-(3- chloropropionyl)-spiro[bicyclo[2.2.2]octane-2,3- piperidine] [cp. Example 11a)] and 5.9 g (0.0488 mole) of N-methylbenzylamine.

EXAMPLE 13 An amount of 2.68 g (0.0123 mole) of spirolbicyclo- [2.2.2]oxtane-2,3-piperidine]-1-acetonitrile is dissolved in 25 ml of abs. ether, and the solution stirred, within 15 20 minutes with ice cooling, into a suspension of 0.63 g (0.0165 mole) of lithium aluminium hydride in 75 ml of abs. ether. The mixture is refluxed in a nitrogen atmosphere for 16 hours. After cooling. dropwise additions are made successively of 1 ml of water, 2 ml of 2N sodium hydroxide solution and a further 1 ml of water. The mixture is then stirred for 1 hour at room temperature, filtered under reduced pressure, and the filter residue subsequently thoroughly washed with ether. The filtrate is dried over sodium sulphate and concentrated by evaporation. There is thus obtained l-(2-aminoethyl)-spiro[bicyclo[2.2.2]octane- 2,3'-piperidine], which is converted with excess ethereal hydrogen chloride solution into 1'-(2-aminoethyl)- spiro[bicyc1o[2.2.2 octane-2,3'-piperidine]- dihydrochloride, 270272 (from methanol/ether).

a. The spirolbicyclol2.2.2]octane-2,3-piperidine]- 1-acetonitrilc serving as starting material is produced analogously to Example 5, starting with 7.1 g (0.040 mole) of spirolbicyclo[2.2.2]octane-2,3-piperidine], 3.6 g (0.048 mole) of chloroacetonitrile and g (ca. 0.07 mole) of anhydrous potassium carbonate.

EXAMPLE 14 4.45 g (0.020 mole) of l'-(2-aminoethyl)- spirolbicyclo[2.2.2]octane-2,3-piperidine] is heated in a mixture of 5.5 g (0.12 mole) of 90% formic acid and 40 ml (ca. 0.53 mole) of 35% aqueous formaldehyde solution, with stirring, for 14 hours at 100. After cooling, the mixture is rendered alkaline with 60 ml of 20% sodium hydroxide solution, and extracted three times with 50 ml of ether each time. The ether extracts are washed separately in each case twice with saturated sodium chloride solution, dried over sodium sulphate and dried in vacuo (ca. 12 Torr). The residue is dissolved in 50 ml of abs. benzene; this is then evaporated off and the treatment with benzene repeated twice. The

crude 1-[Z-(dimethylamino)-ethyl]-spiro [bicyclo[2.- 2.2]octane-2,3'-piperidine] remaining behind is converted, with excess ethereal hydrogen chloride solution, into its dihydrochloride, M.P. 295 (with decomposition).

EXAMPLE 15 v 24.9 g (0.15 mole) of 1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidine] and 25 g of potassium carbonate are suspended in ml of ethanol; an addition of 15.0 g (0.11 mole) of epichlorohydrin (l-chloro-2,3- epoxypropane) is subsequently made. whereupon the mixture heats up to 40. It is stirred for 16 hours at room temperature and then concentrated in vacuo (ca. 12 Torr). The residue is suspended in ml of water, and extracted three times with 50 m1 of chloroform each time. The chloroform extracts are washed separately three times with 50 ml of water each time, dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in 200 ml of 2N hydrochloric acid; this solution is extracted once with 50 ml of chloroform and concentrated in vacuo (ca. 12 Torr). The obtained reddish crystals are recrystallised from acetone/ether to obtain oz-(chloromethyU- (1RS,2RS,4SR)-spiro[norbornane-2,3'-piperidine]-1 -ethanol-hydrochloride, M.P. 199201.

EXAMPLE 16 An amount of 0.6 g (0.026 gram atom) of sodium is dissolved in 150 ml of ethanol; successive additions are then made, to the obtained sodium ethoxide solution, of 5.2 g (0.02 mole) of a-(chloromethyh- (1RS,2RS,4SR)-spiro[norbornane-2,3-piperidine]-1'- ethanol (see Example 15) and 3.5 g of( lRS,2RS,4SR)- spiro]norbornane-2,3-piperidine]. The reaction mixture is subsequently refluxed in a nitrogen atmosphere for 16 hours and, after cooling, concentrated in vacuo (ca. 12 Torr). The residue is suspended with 150 ml of water and extracted three times with 50 ml of chloroform each time. The chloroform extracts are separately washed twice with water; they are then dried over sodium sulphate, and concentrated in vacuo (ca. 12 Torr) to obtain 1.3-bis-((1RS,2RS,4SR)-spiro [norbornane-]2,3'-piperidin]-l -yl)-2-propanol. This is converted with excess ethereal hydrogen chloride into the dihydrochloride which, after recrystallisation from methanol/ether melts'at (with decomposition).

What we claim is:

1. A compound which is 1-(3,4-dich1orobenzy1)- (1RS,2RS,4SR)-spiro[norbornane -2,3 '-piperidine] and its pharmaceutically acceptable acid addition salts.

2. A compound which is 1-[2-( 2- azaspiro[5.5]undec-2-y1)ethyl]-spiro[bicyclo[2.2.- 2]octane-2,3'-piperidine] and its pharmaceutically acceptable acid addition salts.

3. A compound according to claim 2 which is l-[2- (2-azaspiro[5.5]undec-2-y1)-ethyl]-spiro[bicyclo[2.2.- 2]octane-2,3-piperidine] dihydrochloride.

4. A dicarboxylic acid imide of the formula 11 C H C co H c wherein R represents hydrogen, an alkyl group hhaving at most 6 carbon atoms. an optionally chlorinesubstituted hydroxyalkyl group in which the bonds to the ring nitrogen atom, to the hydroxy group and to the optionally present chlorine atom proceed from different carbon atoms, and which contains at least 2 or, if a chlorine atom is present, at least 3 and in both cases at most 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, the 2- propynyl group, a phenyl-(lower alkyl) group optionally mono-to tri-substituted by halogen, lower alkyl or alkoxy groups, or a basic radical of the partial formula la wherein alk stands for a nongeminal, bivalent, saturated aliphatic hydrocarbon radical having 2 to 5 carbon atoms, or for the 2-hydroxy trimethylene radical,

R and R have the meanings given for R with the exception of the radical of the partial formula Ia, or together represent a tetramethylene to hexamethylene radical optionally substituted by lower alkyl groups, the ethyleneoxyethylene radical or a tetraor pentamethylene radical substituted, for its part, in the 2-position by the tetramethylene, pentamethylene, l,4-methanopentamethylene or 1,4- enthanopentamethylene radical,

m represents or 1, and

n represents 1 or 2,

5. A dicarboxylic acid imide according to claim 4 having the formula ll given in claim 4, wherein R, represents a hydrogen atom and m and n have the meanings defined in claim 4.

6. A compound of the formula IV wherein R represents a radical lessened by a methylene group, but otherwise corresponding to the definition for R given in claim 4,

and m and n have the meanings given in claim 4.

7. A compound of the formula V wherein H20 c\ Nalk'-CN (VIII) c l H2 wherein alk represents a bivalent, saturated alphatic hydrocarbon radical having 1 to 4 carbon atoms,

and m and n have the meanings given in claim 4. 

1. A COMPOUND WHICH IS 1''-(3,4-DICHLOROBENZYL)(RS,2RS,4SR)-SPIROL NORBORNANE -23''PIPERIDINE
 2. A compound which is 1''-(2-(2-azaspiro( 5.5)undec-2-yl)ethyl)-spiro(bicyclo(2.2.2)octane-2,3''-piperidine) and its pharmaceutically acceptable acid addition salts.
 3. A compound according to claim 2 which is 1''-(2-(2-azaspiro(5.5)undec-2-yl)-ethyl)-spiro(bicyclo(2.2.2)octane-2,3'' -piperidine) dihydrochloride.
 4. A dicarboxylic acid imide of the formula II
 5. A dicarboxylic acid imide according to claim 4 having the formula II given in claim 4, wherein R1 represents a hydrogen atom and m and n have the meanings defined in claim
 4. 6. A compound of the formula IV
 7. A compound of the formula V
 8. A nitrile of the formula VIII 